The central theme of the Program Project is focused on defining the mechanisms that govem host inflammatory and immune responses at mucosal surfaces in the gastrointestinal tract. The four interrelated projects use microbial pathogens, microbial products, and environmental stress injuries as probes of host intestinal mueosal defense. The program applies state-of-the-art approaches and draws on strengths inherent in human and murine in vitro and in vivo model systems to explore key signaling pathways in host intestinal epithelial cells and macrophages that are required for innate immunity and cell survival. A major focus is placed on defining mechanisms by which bacteria, bacterial products, and mucosal injury signal intestinal epithelial cell and macrophage responses, and mechanisms that are important for the host response to infections with disease-causing noninvasive, minimally invasive and invasive pathogens. The Program brings together experienced investigators from the Departments of Medicine, Pharmacology and Pathology with significant expertise in immunology, molecular biology, biochemistry, and microbiology. Research Unit 1 investigates the functional role and importance of the transcription factor NF-kappaB in intestinal epithelial cells in vivo in regulating intestinal mueosal innate immune responses to microbial pathogens and in preventing epithelial cell apoptosis, as well as the role epithelial NF-kappaB plays in an in vitro model of epithelial cell wound healing. Research Unit 2 examines intestinal mucosal responses and mucosal defense mechanisms that govern the host's interaction with G. lamblia and C. parvum. Research Unit 3 examines epithelial cell signaling mechanisms that are activated by bacterial DNA and the mechanisms by which bacterial DNA can modulate intestinal mueosal innate immunity and mucosal inflammatory responses in vivo. Research Unit 4 examines the role of the transcription factor NF-kappaB in a model of intestinal isehemia reperfusion injury and the mechanisms by which NF-kappaB, together with p3 8 MAP kinase, governs macrophage death and survival in response to microbial products. The research projects are supported by four Cores: a Cell Culture and Assay Core, a Mouse Model Core, a Histopathology Core, and an Administrative Core.